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Nuclear deformation causes DNA damage by increasing replication stress

Pragya Shah, Chad M. Hobson, Svea Cheng, View ORCID ProfileMarshall Colville, Matthew Paszek, Richard Superfine, View ORCID ProfileJan Lammerding
doi: https://doi.org/10.1101/2020.06.12.148890
Pragya Shah
1Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA
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Chad M. Hobson
2Dept. of Physics and Astronomy, University of North Carolina, Chapel Hill, NC 27514, USA
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Svea Cheng
1Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA
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Marshall Colville
3Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY 14853, USA
4Graduate Field of Biophysics, Cornell University, Ithaca, NY 14853, USA
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  • ORCID record for Marshall Colville
Matthew Paszek
3Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY 14853, USA
4Graduate Field of Biophysics, Cornell University, Ithaca, NY 14853, USA
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Richard Superfine
5Dept. of Applied Physical Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
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Jan Lammerding
1Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA
6Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
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  • ORCID record for Jan Lammerding
  • For correspondence: jan.lammerding@cornell.edu
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Summary

Cancer metastasis, i.e., the spreading of tumor cells from the primary tumor to distant organs, is responsible for the vast majority of cancer deaths. In the process, cancer cells migrate through narrow interstitial spaces substantially smaller in cross-section than the cell. During such confined migration, cancer cells experience extensive nuclear deformation, nuclear envelope rupture, and DNA damage. The molecular mechanisms responsible for the confined migration-induced DNA damage remain incompletely understood. While in some cell lines, DNA damage is closely associated with nuclear envelope rupture, we show that in others, mechanical deformation of the nucleus is sufficient to cause DNA damage, even in the absence of nuclear envelope rupture. This deformation-induced DNA damage, unlike nuclear envelope rupture-induced DNA damage, occurs primarily in S/G2 phase of the cell cycle and is associated with replication forks. Nuclear deformation, resulting from either confined migration or external cell compression, increases replication stress, possibly by increasing replication fork stalling, providing a molecular mechanism for the deformation-induced DNA damage. Thus, we have uncovered a new mechanism for mechanically induced DNA damage, linking mechanical deformation of the nucleus to DNA replication stress. This mechanically induced DNA damage could not only increase genomic instability in metastasizing cancer cells, but could also cause DNA damage in non-migrating cells and tissues that experience mechanical compression during development, thereby contributing to tumorigenesis and DNA damage response activation.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵7 Lead contact

  • Updated version with new results and slight modifications to the text.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted October 21, 2020.
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Nuclear deformation causes DNA damage by increasing replication stress
Pragya Shah, Chad M. Hobson, Svea Cheng, Marshall Colville, Matthew Paszek, Richard Superfine, Jan Lammerding
bioRxiv 2020.06.12.148890; doi: https://doi.org/10.1101/2020.06.12.148890
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Nuclear deformation causes DNA damage by increasing replication stress
Pragya Shah, Chad M. Hobson, Svea Cheng, Marshall Colville, Matthew Paszek, Richard Superfine, Jan Lammerding
bioRxiv 2020.06.12.148890; doi: https://doi.org/10.1101/2020.06.12.148890

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